It is well-known in the literature that ethylenically unsaturated hydrophilic monomers with/without additional ethylenically unsaturated hydrophobic monomers can be polymerized to prepare hydrogel polymers. The literature is also replete with studies demonstrating the diffusion of active compounds, e.g., drugs, across a hydrogel membrane to the delivery environment.
U.S. Pat. No. 3,767,790 discloses the preparation of products whereby microorganism(s), e.g., bacteria or yeast, can be entrapped in a hydrophilic polymer, in the form of a powder, tablet, pill or capsule, for release into an environment on which the microorganism(s) can act. Water-swellable polymers of 2-hydroxyethyl methacrylate alone or in combination with acrylamide or vinylpyrrolidone are illustrative of the many polymer matrices disclosed by the patentee.
U.S. Pat. No. 3,808,686 discloses the preparation of an organic solution of a water-insoluble, organic solvent soluble hydrophilic polymer for application to denture prostheses to eliminate denture breath. Among the numerous polymers disclosed are homopolymers of 2-hydroxyethyl methacrylate and of 2-hydroxyethyl acrylate; copolymers of 2-hydroxyethyl acrylate and methyl methacrylate; copolymers of 2-hydroxyethyl methacrylate and vinylpyrrolidone; and others. The patentee discloses the dissolution of the polymer in a suitable non-toxic volatile solvent such as ethyl alcohol to which a water-soluble flavoring agent or fragrance is added.
U.S. Pat. No. 3,780,003 discloses moisture vapor permeable films and coatings of copolymers of hydroxyalkyl methacrylate or of hydroxyalkyl acrylate with alkoxyalkyl methacrylate or of alkoxyalkyl acrylate. Examples include copolymers of 2-hydroxyethyl methacrylate and methoxyethyl acrylate, of 2-hydroxyethyl methacrylate and ethoxyethyl acrylate, and of hydroxyethyl acrylate and ethoxyethyl methacrylate. The polymers, as films and coatings, have utility in adhesive, medical and surgical areas.
U.S. Pat. No. 4,298,002 discloses hydrophilic materials useful in the preparation of chambers and devices for the release of biologically active tissue contained therein. Illustrative polymers include those made from mixtures of 2-hydroxyethyl methacrylate and monomers such as N-vinylpyrrolidone, acrylamide, and others, plus ethylene glycol dimethacrylate as a crosslinking agent.
U.S. Pat. No. 3,660,563 discloses water-soluble polymers containing fragrances, drugs, soaps, etc. entrapped therein. Polymers of hydroxy(C.sub.2 -C.sub.3)alkyl acrylate or of hydroxy(C.sub.2 -C.sub.3)alkyl methacrylate and an ethylenically unsaturated copolymerizable monomer are disclosed. The copolymerizable monomer is employed in an amount sufficient to produce a water-soluble copolymer.
U.S. Pat. No. 4,303,066 discloses particulate water-swellable, water-insoluble, alcohol swellable particulate polymers of hydroxyalkyl acrylate, of hydroxyalkyl methacrylate, of vinylpyrrolidone, and/or of alkoxyalkyl methacrylate. The particulate homopolymer or copolymer is employed in a two package system useful in the formation of a burn dressing.
U.S. Pat. No. 3,641,237 discloses the preparation of hydrophilic polymeric films having good diffusion barriers for water-soluble or water-leachable drugs. The films are prepared by polymerizing at least one alkoxyalkyl methacrylate or alkoxyalkyl acrylate with/without a minor amount of 2-hydroxyethyl methacrylate or hydroxypropyl acrylate.
U.S. Pat. No. 4,517,138 discloses the preparation of hydrogel contact lenses prepared by spincasting a mixture containing 2-hydroxyethyl methacrylate with/without acrylamide.
In the administration of certain pharmaceuticals, long-term drug delivery has been shown to be effective in that constant serum levels are obtained and patient compliance is improved. Delaying the release of the active agent from a drug delivery device is also desirable in that an immediate release upon placement in the delivery environment can result in unacceptably high initial concentrations of a drug at the sites of implantation.
The examination of synthetic hydrogels for potential biomedical applications (including potential use in certain drug delivery devices) has given rise to various theories regarding mechanisms of diffusion. Lee, Jhon and Andrade have proposed that there are three classes of water in hydrogels, using poly(2-hydroxyethyl methacrylate), oftentimes abbreviated as polyHEMA, as their model [Nature of Water in Synthetic Hydrogels, J. Colloid & Interface Sci., 51 (2): 225-231 (1975)]. The first 20% of hydrogel water content, called "Z water", was said to be bound to the polymer matrix. The next 10-12% of water content, called interfacial or "Y water", is partially affected by the polymer matrix. Any additional water imbibed by the gel is relatively unaffected by the polymer matrix; it is called bulk or "X water".
The Lee, et al. model was expanded upon by Kim, Cardinal, Wisniewski and Zentner [Solute Permeation Through Hydrogel Membranes: Hydrophilic vs. Hydrophobic Solutes, ACS Symposium Series (Water in Polymers), 127 (20): 347-359 (1980)]. They concluded that the diffusion coefficients for hydrophilic solutes through hydrogel membranes depends on molecular size and water content; permeation in pure polyHEMA and in polyHEMA crosslinked with a low mole percent of ethylene glycol dimethacrylate was via the pore mechanism, i.e., through the bulk-type water. Hydrophobic solutes were said to diffuse via both pore and partition mechanisms, i.e., respectively through the bulk-type water, and through the interfacial-type and bound-type water.
Wood, Attwood and Collett have described a model for diffusion of the small hydrophobic molecule salicylic acid (the solute) in hydrogels [The Influence of Gel Formulation on the Diffusion of Salicylic Acid in PolyHEMA Hydrogels, J. Pharm. Pharmacol., 34: 1-4 (1982)]. Radioactively labeled salicylic acid was added to a HEMA monomer solution and polymerized in situ. The water contents of the resulting gels were measured. Diffusion was measured by quantifying migration of the solute to a gel placed in contact with the sample gels. It was concluded that diffusion occur ed primarily through the polymer's pores via the hydrating liquid at higher levels of hydration (more than 31%). At hydration levels below 31%, diffusion was said to occur by dissolution of the solute within the polymer segments; crosslinker concentration did not have any significant effect on diffusion. This was correlated to a change in pore size proportional with percent hydration. For another treatment of the interaction of pore size and diffusion, see Wisniewski and Kim [J. Membrane Sci., 6: 299-308 (1980)].
Microporous membranes (some including hydrogels) have been used as rate-limiting barriers for such devices, including implants, ocular inserts, coated intrauterine devices and the like, for example, as described in U.S. Pat. Nos. 3,416,530, 3,618,604, and 3,828,777 to Ness; U.S. Pat. No. 3,551,556 to Kliment, et al; U.S. Pat. No. 4,548,990 to Mueller, et al.
In U.S. Pat. Nos. 3,993,072, 3,948,254, and 3,854,380 to Zaffaroni, drug delivery systems are disclosed including a solid inner matrix containing a drug and surrounded by a wall formed of a polymeric membrane (the '072 and '254 patents call for a microporous membrane, the pores of which contain a drug-release-rate-controlling medium).
Some sustained release devices have been described for the delivery of hydrophilic macromolecules, such as polypeptides. For example, European Patent Application Publication No. 0,092,918 to Churchill, et al. entitled "Continuous Release Formulations" describes the continuous release of, e.g., luteinizing hormone-releasing hormone, growth hormones and growth hormone releasing factor, from a hydrophobic/hydrophilic non-crosslinked copolymer in which the hydrophobic component is biodegradable and the hydrophilic component may or may not be biodegradable. The composition is described as being capable of absorbing water to form a hydrogel when placed in an aqueous, physiological-type environment.
In European Patent Application Publication No. 0246653, publication date Nov. 25, 1987, in the names of Sanders and Domb, there is disclosed a drug delivery device comprising a pharmaceutically acceptable carrier, macromolecules of at least 1000 molecular weight, e.g., luteinizing hormone-releasing hormone polypeptide and analogs thereof, mixed with said carrier, and a non-biodegradable, hydrogel rate-limiting membrane which surrounds or envelopes the drug and carrier. The patent applicants disclose that a ratio of crosslinked and uncrosslinked polymers made from 50-100 mole percent hydrophilic monomers, 0-50 mole percent hydrophobic monomers, and 0-10 mole % crosslinker can be varied to prepare the membrane to the macromolecular composition to be dispensed. The patent applicants state:
"For example, a non-crosslinked hydrophilic homopolymer would be expected to have the largest pore sizes and greatest ability to swell, but ultimately, may tend to dissolve. The addition of crosslinking agent would render the hydrogel somewhat more rigid and limit the swellability of the hydrogel, thereby limiting the expansion of the interstitial spaces. The addition of the hydrophobic comonomer would enhance the restriction even further."
The patent applicant's working examples disclose the preparation of crosslinked and non-crosslinked homopolymers of 2-hydroxyethyl methacrylate and copolymers of 2-hydroxyethyl methacrylate and methyl methacrylate.
Davidson, Domb, Sanders, and McRae disclose that hydrogel membranes of polyHEMA and HEMA/methyl methacrylate copolymer can be used for controlled delivery of analogs of LHRH. Cylindrical implant devices of crosslinked poly(2-hydroxyethyl methacrylate) containing excess LHRH analog (RS-49947) dispersed in silicone oil were implanted in several beagles for one year. Several of the devices, because of the low mechanical strength of the hydrogel polymer, did not remain intact for the whole year; however, of those devices remaining intact estrus was suppressed in the female beagles [Hydrogels for Controlled Release of Peptides, Proceed. Intern. Symp. Cont. Rel. Bioact. Mater., 15, (1988), Controlled Release Society, Inc.].